Complete pain relief after bevacizumab in a patient with neurofibromatosis type 2.

To the Editor, Neurofi bromatosis type 2 is a hereditary tumor predisposition syndrome manifesting with bilateral vestibular schwannomas, schwannomas of other cranial nerves, meningiomas, spinal schwannomas, ependymomas and other gliomas. It is caused by mutations of a tumor suppressor gene called ‘Merlin’ [1]. Surgery and radiation therapy are the only established treatment options [2,3]. Recently, a hearing improvement and a reduction of tumor volume of vestibular schwannomas and intracerebral meningiomas after systemic treatment with bevacizumab have been documented [4–12]. We now report an impressive effect of bevacizumab treatment on symptomatic peripheral schwannomas with a fast and complete pain relief in a patient with neurofi bromatosis type 2.

To the Editor, Neurofi bromatosis type 2 is a hereditary tumor predisposition syndrome manifesting with bilateral vestibular schwannomas, schwannomas of other cranial nerves, meningiomas, spinal schwannomas, ependymomas and other gliomas. It is caused by mutations of a tumor suppressor gene called 'Merlin' [1]. Surgery and radiation therapy are the only established treatment options [2,3]. Recently, a hearing improvement and a reduction of tumor volume of vestibular schwannomas and intracerebral meningiomas after systemic treatment with bevacizumab have been documented [4][5][6][7][8][9][10][11][12]. We now report an impressive effect of bevacizumab treatment on symptomatic peripheral schwannomas with a fast and complete pain relief in a patient with neurofi bromatosis type 2.

Case report
A 27-year-old woman with known neurofi bromatosis type 2 was referred to our outpatient clinics because of symptomatic progression.
According to the Manchester criteria the diagnosis of neurofi bromatosis type 2 was made eight years earlier, at which time the patient presented with bilateral hearing impairment. The radiological fi ndings were consistent with the manifestation of bilateral vestibular schwannomas. In the following years both lesions were treated with stereotactic radiosurgery. Some years later, after a symptomatic progression, the right-sided tumor was treated with a partial resection. Histologically, a schwannoma (WHO grade I) was confi rmed. Additionally, multiple symptomatic spinal and peripheral schwannomas were resected in the following years (Supplementary At the time of admission the patient mainly suffered from progressive left-sided hearing loss and a severe lumbovertebral pain syndrome. The brain magnetic resonance imaging (MRI) showed a progressive lesion in the left cochlear apex. Figure 1 shows a T1-weighted sagittal gadoliniumenhanced MRI of the lumbar spine with numerous partially confl uent schwannomas. Compared to a previous MRI there was a progression of an intraspinal schwannoma at T12/L1 and a newly described schwannoma at L4 with typical features of heterogeneous contrast enhancement and some cystic changes. Due to the high number of schwannomas, no single lesion could be identifi ed as cause for the pain.
Due to the symptomatic multifocal disease progression and particularly the progressive hearing loss we decided to start an intravenous treatment with bevacizumab (5 mg/kg). Before treatment the lumbovertebral pain intensity was severely interfering with daily life even though the patient was on a combined analgetic treatment with opioids, metamizol and gabapentin. Interestingly, only a few days after the fi rst infusion, the patient reported a dramatic reduction and fi nally disappearance of the lumbovertebral pain syndrome. Hence, all analgetic drugs could be stopped within two weeks. In contrast, the follow-up audiometry did not Bevacizumab in a patient with neurofi bromatosis type 2 281 The patient was pain-free without analgetic drugs two weeks thereafter.

Discussion
Neurofi bromatosis type 2 is an inherited disease associated mainly with benign tumors such as schwannomas, meningiomas, ependymomas and other gliomas. A majority of these tumors can be treated with surgery or radiotherapy in the case of symptomatic disease [2,3]. Until recently, systemic therapy had no role in the treatment of neurofi bromatosis type 2. Cytotoxic chemotherapy has no signifi cant impact in these slowly proliferating neoplasms. Therefore, a number of potential therapeutic targets have been investigated taking into account the complex downstream signaling pathways involved in the pathogenesis of this disease [4][5][6][7][8][9][10][11][12].
Whereas vestibular schwannomas are causing hearing defi cits, pain is more often the leading symptom in peripheral schwannomas. This neuropathic pain is often diffi cult to manage and resistant to document a hearing improvement. The treatment was continued for 18 months without pain recurrence. Figure 2 shows MRI follow-up four months after therapy stop with mixed response, but stable disease measured by RECIST 1.1 criteria. The tumor at level T12/L1 had diminished in size, while the tumor at level L4 had increased in size and multiple additional schwannomas were stable in size.
Five months after bevacizumab was stopped the patient became symptomatic again with pain in the lumbovertebral region irradiating into the right leg. The neurological exam excluded sensomotoric defi cits. New pathologic bony lesions were excluded by x-ray. We concluded that again, the known spinal schwannomas caused the pain and reinstalled a treatment with bevacizumab. Before treatment start, the patient was on an analgetic medication with metamizol and gabapentin without any relevant success; 8/10 points were documented on the visual pain scale. After applying the fi rst infusion of bevacizumab the pain decreased again very rapidly (Figure 3). treatment with analgetic drugs. The patient in this case report experienced an impressive and very fast symptomatic response after only one infusion of bevacizumab.
Antiangiogenic therapy targeting VEGF or its receptors modifi es the vascular network by decreasing the number of blood vessels and normalizing the remaining vessels with regard to morphology and functionality. However, the observed effect with a pain relief within a few days most likely is not due to a reduction or normalization of blood vessels with a consecutive effect on the tumor cells. Most likely, the effect of bevacizumab is a consequence of the reduced endothelial permeability and subsequent tumor edema [8]. This is supported by the fact that the mean apparent diffusion coeffi cient (ADC) value of the tumor at baseline is associated with radiographic response in vestibular schwannoma treated with bevacizumab [9].
In summary, we document a dramatic reduction of pain caused by peripheral schwannomas after treatment with bevacizumab in a patient with neurofi bromatosis type 2. These fi ndings may warrant further investigation of bevacizumab in this specifi c clinical situation.

Declaration of interest:
The authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper.

Department of Radiation Oncology, VU University Medical Center, De Boelelaan, HV Amsterdam, The Netherlands
To the Editor, Intensity-modulated radiation therapy (IMRT) is particularly useful for treating irregularly shaped planning target volumes (PTVs) whilst minimizing doses to organs at risk (OARs). Volumetric modulated arc therapy (VMAT) is a form of rotational IMRT that typically requires less delivery time and monitor units (MU) compared to static IMRT beams. Treatment planning aims to create plans with an optimal trade-off between PTV coverage and OAR sparing [1][2][3]. In the search for better VMAT plans there are many parameters that the planner can modify, including the number of arcs. We previously demonstrated that RapidArc ® (Varian Medical Systems, Palo Alto, CA, USA) with two arcs was associated with improved plan quality over a single arc and increased agreement between calculated and measured doses, while beam-on time was still less than 3 minutes [4]. Since the RapidArc optimization algorithm tries to maximize gantry speed we hypothesized that using more than two arcs, which would allow for a longer delivery time and more opportunity for modulation, might translate into further gains in plan quality. We investigated the relationship between the number of arcs, PTV dose homogeneity and OAR sparing.

General considerations
Planning CT scans from 10 patients with head and neck cancer previously treated using RapidArc were selected for this retrospective planning study. The head and neck location was selected because it is a challenging scenario for treatment planning. Plans were created using the current institutional simultaneous integrated boost (SIB) technique described in detail previously [5]. In brief, this aims to deliver 54.25 Gy/70 Gy to the elective/boost PTV (PTV E / PTV B ) in 35 fractions. PTV B consisted of the gross tumor volume and biopsy-proven positive lymph nodes with a 5 mm margin for microscopic disease (edited for anatomical boundaries) and a 4-5 mm PTV margin. PTV E consisted of elective nodal regions, with a 4-5mm PTV margin, minus a 5mm transition zone (PTV T ), which was created between PTV B and PTV E to allow for a steep dose falloff.
OARs with only a maximum dose objective taken into account in the optimization included the brainstem, spinal cord, and their planning at risk volumes (PRV) after 3mm expansion. OAR for which the aim was to reduce the mean dose included salivary structures (e.g. the ipsilateral and contralateral parotid